Effects of grapefruit juice and smoking on verapamil concentrations in steady state

Objective: Human gut wall cytochrome P-450 (CYP)3A4 is inhibited by grapefruit juice (G), whereas smoking increases CYP1A2 activity. Both enzymes contribute to verapamil biotransformation. This study was performed to quantitatively assess the effect of these factors on verapamil pharmacokinetics in steady state. Methods: Twenty-four young healthy volunteers of both sexes (12 smokers, 12 non-smokers) participated in this randomised crossover study. Prolonged release verapamil (120 mg, Isoptin KHK) was given bid for 7 days in two periods. During days 5-7, 11 of either G or water was coadministered daily. On day 7, concentrations of verapamil and norverapamil enantiomers were determined during one dosing interval, and model independent pharmacokinetic parameters were estimated. PR intervals were monitored for pharmacodynamics. Statistical evaluation was done essentially using bioequivalence methods. Results: G significantly increased (R, S)-verapamil the area under the concentration-time curve at steady state (AUC(tau,ss)) by a mean of 1.45-fold [90% confidence interval (CI) 1.29, 1.63] and peak plasma concentration at steady state (C-max,C-ss) by 1.63-fold (90% CI 1.38, 1.91). The increase in concentrations present for (R)- and (S)-enantiomers was slightly greater for verapamil than for norverapamil. Smokers had significantly lower AUC(tau,ss) and C-max,C-ss values than non-smokers by (means) 0.61-fold to 0.85-fold for verapamil and norverapamil enantiomers, respectively. G effects were unrelated to naringenin pharmacokinetics. Prolongation of PR intervals by G coadministration was borderline significant; an increase above 350 ms occurred in two individuals during the G period. Significantly increased urinary 6-beta-hydroxycortisol excretion by G suggests induction of hepatic CYP3A. Conclusions: Patients on verapamil treatment should abstain from grapefruit juice. Smoking habits should be considered for verapamil dosing.